Dextromethorphan Helps When Clozapine Fails in Schizophrenia

REVIEW OF: Hegde NC et al, Asian J Psychiatry 2026;119:104919

STUDY TYPE: Randomized, double-blind, placebo-controlled trial (group sequential design)

EVIDENCE GRADE: Moderate (7/10)

Background

Clozapine is an antipsychotic that can treat schizophrenia when nothing else works, but what do we do when clozapine fails? The few options we have are not supported by rigorous trials and include adding:

• Aripiprazole (10-15 mg qd)
• Topiramate (start 25 mg qd, titrate to max of 200 mg BID)
• Lamotrigine (dose 50–200 mg qd after titration)
• Or switching to another option for treatment resistance, like amisulpride (outside the US) or high-dose olanzapine (25-50 mg qd)

ECT used to be on that list, but has failed in newer trials. Psychotherapy may help. You should also check a clozapine level for pseudoresistance, when the medication is not working because it isn’t getting in their system.

Glutamate dysfunction plays a role in schizophrenia, and this study tested a glutamatergic drug used in depression — dextromethorphan — as an add-on to clozapine.

The Trial

This single-center trial from India randomized 40 adults with treatment-resistant schizophrenia on stable clozapine to add-on dextromethorphan 30 mg/day or placebo for 12 weeks. The trial used a group sequential design with pre-specified interim analyses; recruitment stopped early after the second interim analysis (n=40) crossed the O’Brien-Fleming efficacy boundary.

The dextromethorphan group showed a significantly greater reduction in total PANSS scores compared to placebo (mean difference −10.68 points; bias-adjusted estimate −7.18). Improvements were seen across positive, negative, and general psychopathology subscales. Response rates favored dextromethorphan (75% vs 29%), yielding an number needed to treat (NNT) of 2.19 — meaning 1 out of 2 improved. It’s a striking effect, but effect sizes are often inflated in small studies like this.

The benefits disappeared when tested in a subgroup of patients with pseudoresistance (those who appeared to have a poor response to clozapine but really just had low serum levels). That suggests dextromethorphan is only effective in true clozapine resistance.

Global severity (CGI) and improvement scores also significantly favored the new treatment. Cognitive scores (MMSE) and serum clozapine levels didn’t differ between groups. Although dextromethorphan can cause hallucinations and dissociation in high doses, it did not worsen psychosis in this trial. Adverse events were mild, transient, and comparable between arms.

Practice Implications

1. Dextromethorphan is cheap, widely available, and appears safe at this dose alongside clozapine
2. Risks of dissociation, psychosis, and substance use are concerning, as is the lack of long-term data
3. However, with few options in this population, any credible signal is worth attention

—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report

What’s Your Take? Share in Comments

1. Have you tried dextromethorphan in schizophrenia? What have you seen?